Hereditary Optic Neuropathy Research Articles

Recent advances in neuro-ophthalmology.

This review article represents a collaborative effort across continents, bringing together the latest developments in neuro-ophthalmology with a focus on innovative diagnostic and therapeutic modalities that are shaping the future of the field. Among the most significant advancements is the rise of optical coherence tomography (OCT), now recognized as an indispensable tool in neuro-ophthalmological research, providing unparalleled insights into optic nerve and central nervous system pathologies. Gene therapy, particularly for conditions such as Leber's hereditary optic neuropathy, marks a new frontier in personalized medicine, offering hope for previously untreatable conditions. The article also examines the transformative role of telemedicine and artificial intelligence (AI) in clinical practice, which are revolutionizing patient care and enhancing diagnostic precision. Furthermore, it highlights the impact of novel serological biomarkers on the understanding and management of immune-mediated optic neuritis, and discusses the introduction of new therapeutic agents like Tocilizumab and Teprotumumab, which are redefining treatment paradigms. Collectively, these advancements reflect the profound influence of modern medicine on neuro-ophthalmology, paving the way for improved patient outcomes and fostering new avenues for research and clinical practice.

Clinical and genetic landscape of optic atrophy in 826 families: insights from 50 nuclear genes.

Hereditary optic neuropathies (HON) are a group of diseases due to genetic defects either in mitochondria or in nuclear genomes. The increasing availability of genetic testing has expanded a broader genetic and phenotypic spectrum of HON than previously recognized. To provide systematic insight into the genetic and phenotypic landscape of HON attributed to 50 nuclear genes, we conducted genetic analysis on part of 4776 index patients with clinical diagnosis of HON following our previous study on 1516 probands with Leber hereditary optic neuropathy (LHON) and mitochondrial DNA variants. Exome sequencing was performed in 473 patients diagnosed with nuclear gene-related HON (nHON) and 353 cases with unsolved LHON. Sequencing and variant interpretation in 50 causative nuclear genes indicated that the diagnostic yield of exome sequencing for nHON was 31.50% (149/473), while it was markedly lower at 1.42% (5/353) for LHON patients without primary mtDNA mutations. The top five implicated genes causing nHON in our in-house cohort, OPA1, WFS1, FDXR, ACO2, and AFG3L2, account for 82.46% of mutations. Although OPA1 was the most prevalent causative gene of nHON in both our cohort (53.25%) and literature review (37.09%), the prevalence of OPA1, WFS1, and FDXR differed significantly between our in-house cohort and the literature review (P-adjusted<0.001). Fundus changes in nHON could be stratified into three categories, the most common is optic atrophy at the examination (78.79%), the rarest is LHON-like optic atrophy (3.64%), and the intermediate is optic atrophy with concurrent retinal degeneration (17.57%), which was an independent risk factor for visual prognosis in nHON. A systematic genotype-phenotype analysis highlighted different genetic contributions for ocular, extraocular neurological, and extraocular non-neurological phenotypes. In addition, systemic variant analysis at the individual gene level suggested a revised interpretation of the pathogenicity of a WFS1 heterozygous truncation variant. This study provides a panoramic summary of both the genetic and phenotypic profiles of HON in real-world studies and literature. The category for nHON fundus phenotypes is built for future studies on molecular mechanisms underlying HON and targeted therapies. In addition to routine ophthalmic examinations, careful examination of the extraocular symptoms and meaningful genetic counseling are warranted for patients with nHON.

Childhood Blindness: A Rare Case of Leber Hereditary Optic Neuropathy in a 16-Year-Old Egyptian Patient

Childhood Blindness: A Rare Case of Leber Hereditary Optic Neuropathy in a 16-Year-Old Egyptian Patient

Hypoxia-mediated rescue of retinal ganglion cells deficient in mitochondrial complex I is independent of the hypoxia-inducible factor pathway

Continuous exposure to environmental hypoxia (11% O2) has been shown to markedly slow the progressive degeneration of retinal ganglion cells (RGCs) in a mouse model of mitochondrial optic neuropathy with RGC-specific deletion of the key mitochondrial complex I accessory subunit ndufs4. As a first step toward identifying the therapeutic mechanism of hypoxia in this model, we conducted a series of experiments to investigate the role of the hypoxia-inducible factor (HIF) regulatory pathway in RGC neuroprotection. Vglut2-Cre; ndufs4loxP/loxP mice were crossed with strains bearing floxed alleles of the negative HIF regulatory vhl or of the two major HIF α-subunit isoforms, Hif1α and Hif2α. Deletion of vhl within ndufs4-deficient RGCs failed to prevent RGC degeneration under normoxia, indicating that HIF activation is not sufficient to achieve RGC rescue. Furthermore, the rescue of ndufs4-deficient RGCs by hypoxia remained robust despite genetic inactivation of Hif1α and Hif2α. Our findings demonstrate that the HIF pathway is entirely dispensable to the rescue of RGCs by hypoxia. Future efforts to uncover key HIF-independent molecular pathways induced by hypoxia in this mouse model may be of therapeutic relevance to mitochondrial optic neuropathies such as Leber hereditary optic neuropathy.

A Curious Case of Late Onset Leber’s Hereditary Optic Neuropathy Presenting with Parkinsonism and Longitudinally Extensive Myelopathy

A Curious Case of Late Onset Leber’s Hereditary Optic Neuropathy Presenting with Parkinsonism and Longitudinally Extensive Myelopathy

Anterior Optic Neuropathies without Optic Disc Edema

Anterior optic neuropathies in which the optic discs appear normal include nutritional optic neuropathy, vitamin B12 or folate deficiencies, toxic optic neuropathy due to drugs and heavy metals, and hereditary optic neuropathy. When these conditions become chronic, optic atrophy can occur. Treatment of these diseases, which can cause dramatic vision loss, should be done quickly and permanent neuronal damage should be prevented as much as possible. Therefore, this group of diseases should always be kept in mind by clinicians in cases of unexplained visual loss.

Ganglion Cell Complex Thickness and Visual Function in Chronic Leber Hereditary Optic Neuropathy.

To evaluate the correlation between the macular ganglion cell complex (GCC) thickness measured with manually corrected segmentation and visual function in individuals with chronic Leber hereditary optic neuropathy (LHON). Twenty-six chronic LHON subjects (60% treated with idebenone or Q10) from the Swedish LHON registry were enrolled. Best-corrected visual acuity (BCVA), visual field tests, and optical coherence tomography (OCT) were performed. Visual field was evaluated with the Haag-Streit Octopus 900 with the Esterman test and a custom 30° test. Canon OCT-HS100 scans were exported to the Iowa Reference Algorithm. GCC thickness was obtained after the segmentation was corrected manually in nine macular sectors. The GCC thickness was overestimated by 16 to 30 µm in different macular sectors with the automated segmentation compared with the corrected (P < 0.001). GCC thickness in all sectors showed significant correlation with all functional parameters. The strongest correlation was seen for the external temporal sector (BCVA: r = 0.604, P < 0.001; mean defect: r = 0.457, P = 0.001; Esterman score: r = 0.421, P = 0.003). No differences were seen between treated and untreated subjects with regard to GCC and visual field scores (P > 0.05), but BCVA was better among treated subjects (P = 0.017). The corrected GCC thickness showed correlation with visual function in chronic LHON subjects. The frequently occurring segmentation errors in OCT measurements related to chronic LHON can potentially be misleading in monitoring of disease progression and in evaluating the treatment effects. Precise measurements of GCC could serve as a sensitive tool to monitor structural changes in LHON. We therefore emphasize the importance of careful evaluation of the accuracy of OCT segmentation.

Retinal damage promotes mitochondrial transfer in the visual system of a mouse model of Leber hereditary optic neuropathy

Lenadogene nolparvovec is a gene therapy which has been developed to treat Leber hereditary optic neuropathy (LHON) caused by a point mutation in the mitochondrial NADH dehydrogenase 4 (ND4) gene. Clinical trials have demonstrated a significant improvement of visual acuity up to 5 years after treatment by lenadogene nolparvovec but, surprisingly, unilateral treatment resulted in bilateral improvement of vision. This contralateral effect – similarly observed with other gene therapy products in development for MT-ND4-LHON – is supported by the migration of viral vector genomes and their transcripts to the contralateral eye, as reported in animals, and post-mortem samples from two patients. In this study, we used an AAV2 encoding fluorescent proteins targeting mitochondria to investigate whether these organelles themselves could transfer from the treated eye to the fellow one. We found that mitochondria travel along the visual system (optic chiasm and primary visual cortex) and reach the contralateral eye (optic nerve and retina) in physiological conditions. We also observed that, in a rotenone-induced model of retinal damage mimicking LHON, mitochondrial transfer from the healthy to the damaged eye was accelerated and enhanced. Our results thus provide a further explanation for the contralateral beneficial effect observed during clinical studies with lenadogene nolparvovec.

Recognizing Leber's Hereditary Optic Neuropathy to avoid delayed diagnosis and misdiagnosis.

Leber's Hereditary Optic Neuropathy (LHON) is a maternally inherited optic nerve disease primarily caused by mutations in mitochondrial DNA (mtDNA). The peak of onset is typically between 15 and 30 years, but variability exists. Misdiagnosis, often as inflammatory optic neuritis, delays treatment, compounded by challenges in timely genetic diagnosis. Given the availability of a specific treatment for LHON, its early diagnosis is imperative to ensure therapeutic appropriateness. This work gives an updated guidance about LHON differential diagnosis to clinicians dealing also with multiple sclerosi and neuromyelitis optica spectrtum disorders-related optic neuritis. LHON diagnosis relies on clinical signs and paraclinical evaluations. Differential diagnosis in the acute phase primarily involves distinguishing inflammatory optic neuropathies, considering clinical clues such as ocular pain, fundus appearance and visual recovery. Imaging analysis obtained with Optical Coherence Tomography (OCT) assists clinicians in early recognition of LHON and help avoiding misdiagnosis. Genetic testing for the three most common LHON mutations is recommended initially, followed by comprehensive mtDNA sequencing if suspicion persists despite negative results. We present and discuss crucial strategies for accurate diagnosis and management of LHON cases.

Ocular genetics in the Japanese population.

In today's globalized society, ophthalmologists can examine people of different ethnicities regardless of where they live. The frequency of disease-causing genes varies according to a patient's ethnic background. We explain genetic findings for Japanese patients with inherited eye diseases. Ocular genetics has made great advances over the past 30 years. For example, detecting mutations at nucleotide position 11778 in mitochondrial DNA was useful in the genetic diagnosis of Leber's hereditary optic neuropathy (LHON). I evaluated the genotype-phenotype relationship in cases of corneal dystrophy and inherited retinal dystrophy (IRD). I identified the entire exon sequence of the eyes shut homolog (EYS) gene in patients with autosomal recessive retinitis pigmentosa (RP). EYS gene mutations are the most frequent cause of autosomal recessive RP. RPGRIP1 may be a common causative gene with early-onset severe retinal dystrophy, including Leber congenital amaurosis. However, some genes have complex structures that are difficult to analyze, including the OPN1LW/OPN1MW gene cluster in blue cone monochromacy and the IKBKG/NEMO genes in incontinentia pigmenti. This review will also present two cases with uniparental disomy, a case of IRD with double mutations, and a case with RP complicated with LHON-like neuropathy. Precise understanding of the effects of genetic variants may reveal differences in the clinical characteristics of patients with the same variant. When starting genome medicine, accurately diagnosing the patient, making accurate prediction, determining the genetic pattern, and providing genetic counseling are important. Above all, that both the doctors and patients understand genetic diseases correctly is important.

Hereditary Optic Neuropathies

Hereditary optic neuropathies are a rare disease group, and Leber's Hereditary Optic Neuropathy (LHON), Dominant Optic Atrophy (DOA) and Recessive Optic Atrophies are included in this disease group. These diseases may be isolated or accompanied by other systemic disorders. Leber's Hereditary Optic Neuropathy is the most common hereditary mitochondrial disease. Leber's Hereditary Optic neuropathy presents with acute-subacute, painless vision loss in the 2nd-3rd decade of life, and the other eye is usually affected within 6-8 weeks. Dominant Optic Atrophy is the most common hereditary optic neuropathy and causes slowly progressive, bilateral, symmetric vision loss in the first decade. Recessive optic atrophy begins at an earlier age than DOA, and nystagmus and severe vision loss are observed in these patients. Although there is no definitive treatment for hereditary optic neuropathies today, idebenone treatment and gene therapy for 11778 gene mutation are performed for LHON.

Toxic And Nutritional Optic Neuropathies

Nutritional and toxic optic neuropathies belong to the group of metabolic mitochondrial optic neuropathies together with hereditary optic neuropathies. Nutritional and toxic optic neuropathies are grouped together because they have many common signs and symptoms. Mitochondrial oxidative phosphorylation dysfunction leads to dysfunction of the papillomacular bundle, resulting in optic neuropathy. Common clinical findings include dyschromatopsia, painless bilateral progressive visual loss, central or cecocentral visual field defects, and progressive optic disc pallor. A toxic substance or lacking vitamins and elements critical for mitochondrial function can cause optic neuropathy.

Mitochondrial tRNAGlu 14693A>G Mutation, an "Enhancer" to the Phenotypic Expression of Leber's Hereditary Optic Neuropathy.

Leber's hereditary optic neuropathy (LHON), a maternally inherited ocular disease, is predominantly caused by mitochondrial DNA (mtDNA) mutations. Mitochondrial tRNA variants are hypothesized to amplify the pathogenic impact of three primary mutations. However, the exact mechanisms remained unclear. In the present study, the synergistic effect of the tRNAGlu 14693A>G and ND6 14484T>C mutations in three Chinese families affected by LHON is investigated. The m.14693A>G mutation nearly abolishes the pseudouridinylation at position 55 of tRNAGlu, leading to structural abnormalities, decreased stability, aberrant mitochondrial protein synthesis, and increased autophagy. In contrast, the ND6 14484T>C mutation predominantly impairs complex I function, resulting in heightened apoptosis and virtually no induction of mitochondrial autophagy compared to control cell lines. The presence of dual mutations in the same cell lines exhibited a coexistence of both upregulated cellular stress responses to mitochondrial damage, indicating a scenario of autophagy and mutation dysregulation within these dual-mutant cell lines. The data proposes a novel hypothesis that mitochondrial tRNA gene mutations generally lead to increased mitochondrial autophagy, while mutations in genes encoding mitochondrial proteins typically induce apoptosis, shedding light on the intricate interplay between different genetic factors in the manifestation of LHON.

Preservation of Mitochondrial Function by SkQ1 in Skin Fibroblasts Derived from Patients with Leber's Hereditary Optic Neuropathy Is Associated with the PINK1/PRKN-Mediated Mitophagy.

Increased or altered mitochondrial ROS production in the retinal ganglion cells is regarded as the chief culprit of the disease-causing Leber's hereditary optic neuropathy (LHON). SkQ1 is a rechargeable mitochondria-targeted antioxidant with high specificity and efficiency. SkQ1 has already been used to treat LHON patients, and a phase 2a randomized clinical trial of SkQ1 has demonstrated improvements in eyesight. However, the underlying mechanism of SkQ1 in LHON remains unclear. This study aimed to assess the effects and molecular mechanism of SkQ1 in the preservation of mitochondrial function using skin fibroblasts derived from LHON patients. Our study found that SkQ1 could reduce ROS production and stabilize the mitochondrial membrane. Mechanistically, through network pharmacology and molecular docking, we identified the key targets of SkQ1 as SOD2 and PINK1, which play crucial roles in redox and mitophagy. SkQ1 interacted with PINK1 and downregulated its expression to balance mitochondrial homeostasis. Collectively, the findings of our study reveal that by regulating PINK1/PRKN-mediated mitophagy, SkQ1 preserves mitochondrial function in LHON fibroblasts. The data indicate that SkQ1 may be a novel therapeutic intervention to prevent the progression of LHON.

Leber hereditary optic neuropathy in Slovenia: quality of life and costs from patient perspective

IntroductionLeber hereditary optic neuropathy (LHON) is the most commonly diagnosed mitochondrial disorder, resulting in colour vision abnormalities and rapid but painless deterioration of central vision. While numerous studies have assessed the impact of LHON on the quality of life (QoL) of LHON patients, the financial impact of the disease remains unexplored. This study attempts to calculate both the direct non-medical costs and the indirect costs associated with productivity losses experienced by people with LHON and their unpaid caregivers in Slovenia, in addition to assessing their QoL. Due to the rarity of the disease, the study involved a small sample size, which is important to note for interpreting the results.MethodsThe analysis was conducted on nine adult participants diagnosed with LHON, representing one-third of the total number of known Slovenian patients with this condition. To thoroughly assess the economic and social impact of LHON, tailored questionnaires were designed to collect information on demographics, socioeconomic status, LHON severity, and associated non-medical and indirect costs.ResultsThe mean age of the study participants was 48.8 years (SD 13.3; n = 9). The annual productivity loss attributable to LHON, taking both absenteeism and relative presenteeism into account, was calculated to be EUR 11,608 per person affected. The mean VFQ-25 score, a measure of vision-related quality of life, for adult LHON patients was 30.4 (SD 12.9).ConclusionThe findings highlight the significant economic and social burden of LHON on patients and their families. Ensuring prompt, accurate diagnosis, access to treatment, financial support, and psychological counselling and services are critical to helping individuals cope with and mitigate the profound challenges of vision loss and living with LHON.

Defective post-transcriptional modification of tRNA disrupts mitochondrial homeostasis in Leber’s hereditary optic neuropathy

Leber's Hereditary Optic Neuropathy (LHON) is a rare, maternally inherited eye disease, predominantly due to the degeneration of retinal ganglion cells (RGCs). It is associated with a mitochondrial DNA (mtDNA) point mutation. Our previous study identified that the m.15927G>A homoplasmic mutation damaged the highly conserved basepairing (28C-42G) in anticodon stem of tRNAThr, caused deficient t6A modification and significantly decreased efficiency in aminoacylation and steady-state levels of tRNAThr, and led to mitochondrial dysfunction. Meanwhile, mechanisms underlying mtDNA mutations regulate intracellular signaling related to the mitochondrial and cellular integrity are less explored. Here, we manifested that defective nucleotide modification induced by the m.15927G>A mutation interfered with the expression of nuclear genes involved in cytoplasmic proteins essential for oxidative phosphorylation system (OXPHOS), thereby impacting the assemble and integrity of OXPHOS complexes. As a result of these mitochondrial dysfunctions, there was an imbalance in mitochondrial dynamics, particularly distinguished by an increased occurrence of mitochondrial fission. Excessive fission compromised the autophagy process, including initiation phase, formation and maturation of autophagosome. Both Parkin-mediated mitophagy and receptor-dependent mitophagy were significantly impaired in cybrids haboring the m.15927G>A mutation. These changes facilitated intrinsic apoptosis, as indicated by increased cytochrome c release and elevated levels of apoptosis-associated proteins (e.g., BAK, BAX, cleaved caspase 9, cleaved caspase 3, and cleaved PARP) in the mutant cybrids. This study demonstrates that the m.15927G>A mutation contributes to LHON by dysregulating OXPHOS biogenesis, aberrant quality control, increased autophagy, inhibited mitophagy, and abnormal apoptosis.

Recreating Leber’s Hereditary Optic Neuropathy in iPS derived Neurons: Shedding Light on Pathogenic Mechanisms to Combat Blindness

Recreating Leber’s Hereditary Optic Neuropathy in iPS derived Neurons: Shedding Light on Pathogenic Mechanisms to Combat Blindness

Genetic variants of NQO1 affect the expression and activity of the protein, which determines the efficacy of idebenone treatment in Leber's hereditary optic neuropathy

Genetic variants of NQO1 affect the expression and activity of the protein, which determines the efficacy of idebenone treatment in Leber's hereditary optic neuropathy

Neuroimaging changes in the pregeniculate visual pathway and chiasmal enlargement in Leber hereditary optic neuropathy

PurposeTo describe the pattern of MRI changes in the pregeniculate visual pathway in Leber hereditary optic neuropathy (LHON).MethodThis retrospective observational study enrolled 60 patients with LHON between January 2015 and...

Leber’s Hereditary Optic Neuropathy with Retinal Hemorrhage

ABSTRACT Leber’s hereditary optic neuropathy (LHON) causes subacute visual loss, and, in the acute phase, the optic disc shows hyperemia, peripapillary telangiectasia, and swelling of the retinal nerve fiber layer (RNFL). Rarely, retinal hemorrhage may be present. In this study, we investigated LHON cases with retinal hemorrhage in the acute phase. Among 82 cases (164 eyes) of LHON who visited the Inoue Eye Hospital, retinal hemorrhage was observed in 5 cases (5 eyes). The age at onset was 36 (27–46) years, with 4 male cases. Mitochondrial DNA analysis revealed the presence of the m.11778G > A variant in four patients and the m.14484T > C variant in one patient. There was no medical history and no excessive smoking or alcohol consumption in any of the cases. In all cases, retinal hemorrhages were observed in the RNFL, accompanying the characteristic optic disc findings of LHON. Fluorescein angiography performed in three cases showed no leakage from the optic disc or blood vessels. While rare, the presence of retinal hemorrhage along the RNFL during the acute phase of LHON should be recognized, as it may warrant consideration of alternative diagnoses.